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1.
J Am Acad Dermatol ; 87(3): 551-558, 2022 09.
Article in English | MEDLINE | ID: mdl-35104588

ABSTRACT

BACKGROUND: Congenital nail matrix nevi (NMN) are difficult to diagnose because they feature clinical characteristics suggestive of adult subungual melanoma. Nail matrix biopsy is difficult to perform, especially in children. OBJECTIVE: To describe the initial clinical and dermatoscopic features of NMN appearing at birth (congenital) or after birth but before the age of 5 years (congenital-type). METHODS: We conducted a prospective, international, and consecutive data collection in 102 hospitals or private medical offices across 30 countries from 2009 to 2019. RESULTS: There were 69 congenital and 161 congenital-type NMNs. Congenital and congenital-type NMN predominantly displayed an irregular pattern of longitudinal microlines (n = 146, 64%), reminiscent of subungual melanoma in adults. The distal fibrillar ("brush-like") pattern, present in 63 patients (27.8%), was more frequently encountered in congenital NMN than in congenital-type NMN (P = .012). Moreover, congenital NMN more frequently displayed a periungual pigmentation (P = .029) and Hutchinson's sign (P = .027) than did congenital-type NMN. LIMITATIONS: Lack of systematic biopsy-proven diagnosis and heterogeneity of clinical and dermatoscopic photographs. CONCLUSION: Congenital and congenital-type NMN showed worrisome clinical and dermatoscopic features similar to those observed in adulthood subungual melanoma. The distal fibrillar ("brush-like") pattern is a suggestive feature of congenital and congenital-type NMN.


Subject(s)
Melanoma , Nail Diseases , Nevus , Skin Neoplasms , Adult , Child , Child, Preschool , Dermoscopy , Diagnosis, Differential , Humans , Infant, Newborn , Melanoma/diagnostic imaging , Melanoma/pathology , Nail Diseases/diagnostic imaging , Nail Diseases/pathology , Nevus/diagnosis , Prospective Studies , Skin Neoplasms/diagnostic imaging , Skin Neoplasms/pathology
2.
J Am Acad Dermatol ; 78(4): 760-768, 2018 04.
Article in English | MEDLINE | ID: mdl-28947295

ABSTRACT

BACKGROUND: Subungual squamous cell carcinoma (SSCC) and subungual melanoma (SUM) are rare tumors. Several case reports of association of SSCC with SUM (SSCC-SUM) have been published. OBJECTIVE: We sought to document the clinical, dermoscopic, and histologic features in a case series of SSCC-SUMs and describe their relative frequency compared with those of SSCC and SUM. METHODS: All patients who underwent surgical exploration of the nail apparatus with a dermatopathologic examination from 2012 to 2015 were reviewed retrospectively to identify all cases of SSCC, SUM, and SSCC-SUM. For patients with SSCC-SUM, clinical characteristics were obtained from electronic medical records. All histologic specimens were reviewed by 3 dermatopathologists. RESULTS: The medical records of 456 patients were reviewed. SSCC was diagnosed in 78 (17%), SUM was diagnosed in 63 (14%), and SSCC-SUM was diagnosed in 9. Patients with SSCC-SUM accounted for 11% of those with a diagnosis of SSCC (9 of 78) and 14% of those with a diagnosis of SUM (9 of 63). LIMITATIONS: This was a single-institution retrospective study. CONCLUSION: The association of SSCC and SUM is relatively frequent in patients with SUM and warrants further consideration to understand the underlying mechanisms involved.


Subject(s)
Carcinoma, Squamous Cell/pathology , Melanoma/pathology , Nail Diseases/pathology , Neoplasms, Multiple Primary/pathology , Skin Neoplasms/pathology , Aged , Carcinoma, Squamous Cell/epidemiology , Female , Humans , Male , Melanoma/epidemiology , Nail Diseases/epidemiology , Neoplasms, Multiple Primary/epidemiology , Retrospective Studies , Skin Neoplasms/epidemiology
3.
Acta Derm Venereol ; 97(10): 1219-1224, 2017 Nov 15.
Article in English | MEDLINE | ID: mdl-28761960

ABSTRACT

Facial melanoma is difficult to diagnose and dermatoscopic features are often subtle. Dermatoscopic non-melanoma patterns may have a comparable diagnostic value. In this pilot study, facial lesions were collected retrospectively, resulting in a case set of 339 melanomas and 308 non-melanomas. Lesions were evaluated for the prevalence (> 50% of lesional surface) of 7 dermatoscopic non-melanoma features: scales, white follicles, erythema/reticular vessels, reticular and/or curved lines/fingerprints, structureless brown colour, sharp demarcation, and classic criteria of seborrhoeic keratosis. Melanomas had a lower number of non-melanoma patterns (p< 0.001). Scoring a lesion suspicious when no prevalent non-melanoma pattern is found resulted in a sensitivity of 88.5% and a specificity of 66.9% for the diagnosis of melanoma. Specificity was higher for solar lentigo (78.8%) and seborrhoeic keratosis (74.3%) and lower for actinic keratosis (61.4%) and lichenoid keratosis (25.6%). Evaluation of prevalent non-melanoma patterns can provide slightly lower sensitivity and higher specificity in detecting facial melanoma compared with already known malignant features.


Subject(s)
Decision Support Techniques , Dermoscopy , Facial Neoplasms/pathology , Skin Neoplasms/pathology , Skin/pathology , Algorithms , Diagnosis, Differential , Facial Neoplasms/epidemiology , Humans , Italy/epidemiology , Pilot Projects , Predictive Value of Tests , Prevalence , Retrospective Studies , Skin Neoplasms/epidemiology
5.
Biomedicines ; 11(1)2022 Dec 29.
Article in English | MEDLINE | ID: mdl-36672591

ABSTRACT

Background: ICIs have dramatically improved patient outcomes in different malignancies. However, the impact of liver metastases (LM) and number of metastatic sites (MS) remains unclear in patients treated with single-agent anti-PD(L)1. Methods: We aimed to assess the prognostic impact of LM and MS number on progression-free survival (PFS) and overall survival (OS) in a large single-arm retrospective multicentric cohort (IMMUCARE) of patients treated with anti-PD(L)-1 for different solid tumors. Results: A total of 759 patients were enrolled from January 2012 to October 2018. The primary tumor types were non-small cell lung cancer (71%), melanoma (19%), or urologic cancer (10%). At the time of ICI initiation, 167 patients (22%) had LM and 370 patients (49%) had more than MS. LM was associated with a shorter median PFS of 1.9 months (95% CI: 1.8−2.5) vs. 4.0 months (95% CI: 3.6−5.4) in patients without LM (p < 0.001). The median OS of patients with LM was of 5.2 months (95% CI: 4.0−7.7) compared with 12.8 months (95% CI: 11.2−15.1) (p < 0.001). Interestingly, LM were not associated with shorter PFS, or OS compared to other MS types (brain, bone, or lung) in patients with only one MS. Patients with multiple MS also had poor clinical outcomes compared to patients with only one MS. The presence of LM and MS number were independent prognostic factors on overall survival. Conclusion: The presence of LM or multiple MS were associated with poorer survival outcomes in patients treated with anti-PD(L)-1.

6.
Cancer Med ; 10(10): 3155-3164, 2021 05.
Article in English | MEDLINE | ID: mdl-33932099

ABSTRACT

BACKGROUND: Cytotoxic chemotherapy (CC) is currently used in metastatic melanoma after patients have developed resistance to immune checkpoint inhibitors (ICI) and/or Mitogen-Activated Protein Kinase inhibitors (MAPKi). We sought to evaluate if a previous treatment by ICI or MAPKi influences clinical outcomes in patients treated by CC in metastatic melanoma. METHODS: Eighty-eight patients with a metastatic melanoma, treated by CC after a previous treatment by ICI or MAPKi between January 2009 and October 2019, were retrospectively analyzed. Progression-Free-Survival (PFS), Overall Survival (OS), Overall Response Rate (ORR), and Disease Control Rate (DCR) were evaluated in patients treated by CC according to their prior treatment by ICI or MAPKi. RESULTS: Patients treated by CC after ICI tended to have a better median PFS (2.81 months (2.39-5.30) versus 2.40 months (0.91-2.75), p = 0.023), median OS (6.03 months (3.54-11.54) versus 4.44 months (1.54-8.59), p = 0.27), DCR (26.0% vs. 10.5%, p = 0.121) and ORR (22.0% vs. 7.9% p = 0.134) than those previously treated by MAPKi. CONCLUSIONS: A prior treatment by an MAPKi may be associated with a worse response to CC than ICI, and further investigations should be performed to confirm if there is a clinical benefit to propose CC in this setting.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Melanoma/immunology , Aged , Female , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Male , Progression-Free Survival , Protein Kinase Inhibitors/therapeutic use , Retrospective Studies
7.
Cancers (Basel) ; 13(10)2021 May 14.
Article in English | MEDLINE | ID: mdl-34068892

ABSTRACT

It remains unclear whether immune-related adverse events (irAEs) and glucocorticoid use could impact long-term outcomes in patients treated for solid tumors with immune checkpoint inhibitors (ICI). All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective unicentric study. The objectives were to assess the impact of grade ≥3 irAEs, glucocorticoid use and the interruption of immunotherapy on progression-free survival (PFS) and overall survival (OS). In this 828-patient cohort, the first occurrence of grade ≥3 irAEs had no significant impact on PFS or OS. Glucocorticoid administration for the irAEs was associated with a significantly shorter PFS (adjusted HR 3.0; p = 0.00040) and a trend toward shorter OS. ICI interruption was associated with a significantly shorter PFS (adjusted HR 3.5; p < 0.00043) and shorter OS (HR 4.5; p = 0.0027). Glucocorticoid administration and ICI interruption were correlated. In our population of patients treated with single agent ICI, grade ≥3 irAEs did not impact long-term outcomes. However, the need for glucocorticoids and the interruption of immunotherapy resulted in poorer long-term outcomes. The impact of grade ≥3 irAEs reported in other studies might then be explained by the management of the irAEs.

8.
Eur J Cancer ; 132: 61-70, 2020 06.
Article in English | MEDLINE | ID: mdl-32334337

ABSTRACT

BACKGROUND: The impact of immune-related adverse events (irAE) on survival outcomes after single-agent immune checkpoint inhibitors (ICIs) remains unclear. We aimed to evaluate the association between irAEs and ICI efficacy in various malignancies. METHODS: All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective multicentric series. The primary objective was to assess the impact of all type grade ≥II irAEs on progression-free survival (PFS) and overall survival (OS). IrAEs were first considered as a fixed covariate and included in Cox-regression models. In addition, as irAEs are time-related events and can occur at any point during follow-up, we analysed the occurrence of irAEs as a time-varying covariate. RESULTS: In this cohort of 410 patients, the majority of patients (70%) were treated for non-small cell lung cancer. The ICI was an anti-PD(L)1 for 356 patients (82%) and an anti-CTLA4 for 79 patients (18%). In total 126 (29%) of the patients presented at least one grade ≥II irAEs. The first occurrence of a grade ≥II irAE had a positive impact on PFS and OS when considered as a fixed or as a time-varying covariate (hazard ratio [HR] for PFS = 0.63, 95% confidence interval [CI] 0.50-0.81; P = 0.00022; HR for OS = 0.57, 95% CI 0.43-0.74, P < 0.0001). This overall finding was confirmed in patients treated with an anti-PD(L)1 and among patients with lung cancer. CONCLUSION: In this pooled multi-institutional cohort, the incidence of irAEs was associated with better long-term survival across different malignancies treated with ICI monotherapy.


Subject(s)
Antineoplastic Agents, Immunological/adverse effects , B7-H1 Antigen/antagonists & inhibitors , CTLA-4 Antigen/antagonists & inhibitors , Drug-Related Side Effects and Adverse Reactions/mortality , Neoplasms/mortality , Aged , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasms/drug therapy , Neoplasms/pathology , Prognosis , Retrospective Studies , Survival Rate
9.
Eur J Cancer ; 121: 192-201, 2019 11.
Article in English | MEDLINE | ID: mdl-31590080

ABSTRACT

BACKGROUND: Age-related immune dysfunction might impair the efficacy of immune checkpoint inhibitors (ICIs) in older patients. We aimed to evaluate the impact of age on clinical outcomes and tolerance of ICIs in a real-life setting. METHODS: All patients receiving a single-agent ICI (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] or programmed death(ligand)1 [PD(L)-1] inhibitors) for the standard treatment of a locally advanced or metastatic cancer were included in this retrospective multicentric series. The primary end-point was overall survival (OS). Progression-free survival (PFS) and immune-related adverse events (irAEs) were secondary end-points. The impact of age was assessed using the threshold of 70 years. RESULTS: A total of 410 patients were included, for 435 lines of treatment, including 150 lines (34%) given to patients aged 70 years or older. The primary tumour types were lung cancer (n = 304, 74%), melanoma (n = 79, 19%) and urologic cancer (n = 27, 7%). Most of the administered treatments were PD(L)-1 inhibitors (n = 356, 82%). Median follow-up reached 46 months in the CTLA-4 cohort, and 20 months in the PD(L)-1 cohort. In both treatment cohorts, age did not impact OS (respectively, HR = 0.82, 95% CI 0.5-1.4; log-rank P = 0.49 and HR = 0.9, 95% CI 0.7-1.1; log-rank P = 0.27) or PFS (HR = 0.7, 95% CI 0.4-1.1; log-rank P = 0.13 and HR = 0.9, 95% CI 0.7-1.1; log-rank P = 0.19). Grade 3-4 irAEs rates were not statistically different between older and younger patients (11% vs 12%, P = 0.87). CONCLUSION: In a large real-world series of patients treated by ICI monotherapy, the long-term clinical outcomes were not statistically different between older or younger patients, with no increased immune-related toxicity.


Subject(s)
Aging/physiology , Antineoplastic Agents, Immunological/therapeutic use , Neoplasms/diagnosis , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Age Factors , Aged , Aged, 80 and over , Antibodies, Monoclonal/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Cell Cycle Checkpoints/immunology , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Humans , Male , Middle Aged , Neoplasms/mortality , Neoplasms/pathology , Prognosis , Retrospective Studies , Survival Analysis , Treatment Outcome
10.
Cardiovasc Intervent Radiol ; 42(2): 304-307, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30327928

ABSTRACT

Surgical curettage is currently the standard of care for the chondroblastoma, but in peri-articular tumors it is limited by its morbidity. In this preliminary report, we evaluate the feasibility of percutaneous cryotherapy as an alternative ablative treatment for chondroblastoma. Three patients with a chondroblastoma treated by CT scan-guided cryotherapy are presented in this article. Pain permanently disappeared 2 days after the procedure. No local tumor recurrence or cartilage damage was observed by MRI performed 1 year after the intervention. This preliminary case report suggests that percutaneous cryotherapy may be a possible alternative to the current standard of care in chondroblastoma. Further studies are needed to evaluate if this technique offers similar anti-tumoral efficacy while providing better pain relief and less morbidity than curettage.


Subject(s)
Bone Neoplasms/therapy , Chondroblastoma/therapy , Cryotherapy/methods , Adolescent , Bone and Bones/diagnostic imaging , Female , Follow-Up Studies , Humans , Knee/diagnostic imaging , Magnetic Resonance Imaging/methods , Male , Radiography, Interventional/methods , Tomography, X-Ray Computed/methods
11.
Nat Med ; 25(4): 620-627, 2019 04.
Article in English | MEDLINE | ID: mdl-30833748

ABSTRACT

Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS1-4. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA6. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers.


Subject(s)
Autophagy/drug effects , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , ras Proteins/metabolism , Animals , CA-19-9 Antigen/metabolism , Cell Line, Tumor , Chloroquine/pharmacology , Humans , Mice, SCID , Mitogen-Activated Protein Kinase Kinases/metabolism , Proto-Oncogene Proteins B-raf/metabolism , Pyridones/pharmacology , Pyrimidinones/pharmacology , Xenograft Model Antitumor Assays , Pancreatic Neoplasms
12.
Nat Med ; 25(5): 861, 2019 May.
Article in English | MEDLINE | ID: mdl-30918364

ABSTRACT

In the version of this article initially published, the label over the bottom schematic in Fig. 1a was "pH > 5.0"; it should have been "pH < 5.0". Further, the original article misspelt the surname of Katrin P. Guillen as "Gullien". These errors have been corrected in the print, PDF and HTML versions of the article.

13.
JAMA Dermatol ; 154(1): 82-87, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29214290

ABSTRACT

Importance: Melanoma treatment has been revolutionized with the development of immune-based therapies that offer durable clinical responses in a subset of patients. Clinical outcomes after treatment by immunotherapy can be influenced by the host's immune system. The immune system is modified with age by age-related immune dysfunction. Objective: To evaluate if age influences clinical outcome and immune adverse events in patients treated by immunotherapy for metastatic melanoma. Design, Setting, and Participants: This was a single-center cohort analysis in patients treated with immunotherapy for metastatic melanoma between January 2007 and February 2016, in the Lyon Sud Hospital, France. A total of 92 patients with metastatic melanoma treated with ipilimumab, nivolumab, or pembrolizumab were retrospectively analyzed. Main Outcomes and Measures: Overall survival, progression-free survival, and immune-related adverse events were evaluated for each treatment line according to the patients' age. Results: A total of 92 patients were eligible and included in this study for a total of 120 lines of treatment. Fifty-four patients were included in the cohort that was 65 years or younger (24 [44%] were female; mean [SD] age, 48.1 [12.5] years), and 38 patients were included in the cohort that was older than 65 years (12 [34%] were female; mean [SD] age, 74.8 [6.9] years). Mean follow-up duration starting at treatment initiation was 12.5 months. Patients older than 65 years treated with immunotherapy had a better mean progression-free survival (4.8 vs 3.4 months; P = .04) and overall survival (not reached vs 10.1 months; P = .009) than younger patients in univariate analysis, and after adjusting on prognosis covariates. This was particularly true with patients treated with anti-programmed cell death protein 1. Common immune-related adverse effects were similar in both cohorts. Conclusions and Relevance: Age might be associated with a better clinical outcome after treatment with immunotherapy in the real-life setting. In our cohort, older patients did not have more immune-related adverse events. Further studies are warranted to confirm our results and describe the underlying mechanisms involved.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Melanoma/drug therapy , Melanoma/immunology , Skin Neoplasms/drug therapy , Skin Neoplasms/immunology , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Cohort Studies , Female , France , Geriatric Assessment , Humans , Immunotherapy/methods , Ipilimumab/administration & dosage , Kaplan-Meier Estimate , Male , Melanoma/mortality , Melanoma/pathology , Neoplasm Invasiveness/pathology , Neoplasm Staging , Nivolumab/administration & dosage , Prognosis , Retrospective Studies , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Statistics, Nonparametric , Treatment Outcome
14.
Ther Adv Med Oncol ; 9(7): 481-492, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28717400

ABSTRACT

The disease course of BRAF (v-raf murine sarcoma viral oncogene homolog B1)-mutant melanoma has been drastically improved by the arrival of targeted therapies. NRAS (neuroblastoma RAS viral oncogene homolog)-mutated melanoma represents 15-25% of all metastatic melanoma patients. It currently does not have an approved targeted therapy. Metastatic patients receive immune-based therapies as first-line treatments, then cytotoxic chemotherapy like carboplatin/paclitaxel (C/P), dacarbazine (DTIC) or temozolomide (TMZ) as a second-line treatment. We will review current preclinical and clinical developments in NRAS-mutated melanoma, and analyze ongoing clinical trials that are evaluating the benefit of different targeted and immune-based therapies, either tested as single agents or in combination, in NRAS-mutant melanoma.

15.
Expert Opin Pharmacother ; 17(7): 1005-11, 2016.
Article in English | MEDLINE | ID: mdl-26999478

ABSTRACT

INTRODUCTION: Cobimetinib combined with vemurafenib is a new approved MEK inhibitor for first line treatment of metastatic melanoma patients with BRAF V600 mutations. It improves tumor response rates and progression free survival compared to vemurafenib alone, while decreasing toxicities due to the paradoxical activation of the MAPK signaling pathway. AREAS COVERED: This review covers the pharmacology, efficacy, and toxicity data derived from clinical and preclinical studies on cobimetinib. It also reports ongoing trials evaluating cobimetinib to better understand future developments for this drug. EXPERT OPINION: The combination of cobimetinib and vemurafenib seems to be more toxic than the combination therapy dabrafenib and trametinib even if these four drugs have never been compared in a randomized trial. The future of this combination depends on its capacity to be combined simultaneously or sequentially with immune based therapies to improve the durability of responses.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Azetidines/administration & dosage , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Disease-Free Survival , Humans , Indoles/administration & dosage , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Melanoma/genetics , Mutation , Piperidines/administration & dosage , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/genetics , Sulfonamides/administration & dosage , Vemurafenib
17.
EMBO Mol Med ; 8(10): 1143-1161, 2016 10.
Article in English | MEDLINE | ID: mdl-27596438

ABSTRACT

Targeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF-mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAFV600-mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITFlow/p75high stem-like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Plasticity , Drug Resistance , Melanocytes/drug effects , Melanocytes/physiology , Protein Kinase Inhibitors/pharmacology , Zinc Finger E-box-Binding Homeobox 1/metabolism , Adaptation, Physiological , Cell Line, Tumor , Humans , Melanoma/drug therapy , Melanoma/physiopathology
18.
JAMA Dermatol ; 151(8): 847-53, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25902339

ABSTRACT

IMPORTANCE: Dermoscopy permits the detection of early-stage melanomas but is difficult to learn. It is important to develop effective teaching methods. Spaced education is a methodology within the field of adaptive learning that uses online tools to reinforce long-term retention. OBJECTIVES: To determine whether a spaced education dermoscopy module improved dermoscopy skills in the continuing medical education setting and to evaluate participant satisfaction. DESIGN, SETTING, AND PARTICIPANTS: We designed a prospective controlled study with 2 sequential cohorts of participants enrolled between September 2010 and September 2013, in the continuing medical education dermoscopy program of the Claude Bernard-Lyon 1 University in Lyon, France. Participants enrolled in this program were either certified dermatologists or senior dermatology residents. The control group (n = 95) comprised all participants enrolled during the 2 first years of the study (49 participants in the class of 2010, 46 in the class of 2011). The intervention group (n = 96) comprised all participants enrolled during the third and fourth years of the study (46 in the class of 2012; 50 in the class of 2013). INTERVENTIONS: All participants attended a 3-day lecture followed by small-group tutorials 4 months later. Each participant also attended a day of consultation with a dermoscopy specialist. In addition, participants in the intervention group were enrolled in an e-learning spaced education dermoscopy program. MAIN OUTCOMES AND MEASURES: The main outcome measure was mean participant scores at the posttest evaluation, which was conducted 4 months after course enrollment. RESULTS: The intervention group had better results at the posttest, with a mean (SD) score (out of a possible 160.0 points) of 148.1 (5.8) (n = 82 participants) vs 145.7 (7.7) (n = 90 participants) in the control group (P = .02). Ninety-two percent of the participants (80 of 87) were extremely or very satisfied with the e-learning module. Participant engagement was high, with an average of 85% of participants (80 of 94) "on track" at any given time of the year. CONCLUSIONS AND RELEVANCE: Our study shows that, in the context of continuing medical education, a spaced education Internet dermoscopy module combined with in-class training increases participant performances in dermoscopy. It is easy to use and adaptable to professional working schedules.


Subject(s)
Dermatology/education , Dermoscopy/education , Education, Medical, Continuing/methods , Internet , Adult , Computer-Assisted Instruction , Female , France , Humans , Male , Middle Aged , Prospective Studies
19.
Lung Cancer ; 79(3): 318-20, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23261230

ABSTRACT

Cowden's syndrome is a rare autosomal dominant disorder that has been linked to germline mutations in the phosphatase and TENsin homolog (PTEN) gene. PTEN is a tumour suppressor gene that negatively regulates the PI3K-AKT-mTOR pathway. Cowden's syndrome is a multi-system disease with increased risks for a number of malignancies but very rarely for lung cancer. A systematic follow-up chest CT scan was performed to a 42 year's old female, light smoker. It showed a 20mm opacity of the left upper pulmonary lobe. Differential diagnose with benign tumours (such as hamartoma) was carefully searched. Procedures led to the diagnosis of a primitive lung adenocarcinoma. EGFR sequencing shows two rare somatic mutations (S768I and V769L). Lack of expression of PTEN is a non-sufficient condition leads to lung cancer formation alone. Nevertheless, it increases cell oncogenic potential. PTEN lacking in non small cell lung cancer is a frequent issue. It could be an alternative mechanism of non-efficacy of EGFR-TKI in cells with a sensitizing EGFR mutation. This case report, a very rare entity: a patient with a PTEN germline mutation and a lung adenocarcinoma harbouring two concomitant rare somatic mutations of EGFR. This observation comforts PTENs role in lung oncogenesis.


Subject(s)
Adenocarcinoma/genetics , ErbB Receptors/genetics , Hamartoma Syndrome, Multiple/genetics , Lung Neoplasms/genetics , PTEN Phosphohydrolase/genetics , Adenocarcinoma/complications , Adult , Chromosome Disorders/genetics , DNA Mutational Analysis , Diagnosis, Differential , Female , Germ-Line Mutation , Hamartoma Syndrome, Multiple/complications , Humans , Lung Neoplasms/complications , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Serine/genetics , Signal Transduction/genetics , Valine/genetics
20.
Bull Cancer ; 99(10): 943-52, 2012 Oct.
Article in French | MEDLINE | ID: mdl-23034429

ABSTRACT

To improve the quality of reporting of randomized clinical trials (RCTs), international registries for RCTs and guidelines for primary endpoint (PEP) analysis were established. The objectives of this systematic review were to evaluate concordance of PEP between publication and the corresponding registry and to assess the intrapublication consistency in PEP reporting. All adult oncology RCTs in solid tumors published in 10 journals between 2005 and 2009 were reviewed. Registration information was extracted from international trial registries. A total 366 RCTs were identified. Trial registration was found for 215 trials and the rate increased from 43% in 2005 to 82% in 2009 (P < 0.001). There were 134 RCTs with clearly defined PEPs in registry, with the rate increasing from 15 to 67% (P < 0.001). PEP differs between registration and final publication in 14% trials with clearly defined PEPs. Reporting issues in methodology were found in 15% RCTs, mainly due to inadequate reporting of PEP or of sample size calculation. Problems with the interpretation of trial results were found in 22% publications, mostly due to negative superiority studies being interpreted as showing equivalence. The rates of trial registration and of trials with clearly defined PEP have improved over time, however 14% of these trials reported a different PEP in the final publication. Intrapublication inconsistencies in PEP reporting are frequent. Our findings highlight the need for investigators, peer reviewers and readers for increased awareness and scrutiny of reporting outcomes of oncology RCTs.


Subject(s)
Guidelines as Topic/standards , Medical Oncology/standards , Publishing/standards , Randomized Controlled Trials as Topic/standards , Registries , Research Report/standards , Adult , Humans , Publishing/statistics & numerical data , Quality Assurance, Health Care/methods , Randomized Controlled Trials as Topic/statistics & numerical data , Registries/statistics & numerical data , Treatment Outcome
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